PROJECT SUMMARY/ABSTRACT: MECHANISMS OF RESISTANCE TO ENDOCRINE THERAPY IN ER+ BREAST CANCER Estrogen receptor positive (ER+) breast cancer is the most common subtype of breast cancer, but ~20% of ER+ tumors recur during or following adjuvant endocrine therapy, accounting for ~50% of breast cancer deaths in the US each year. The CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib have been recently approved in combination with endocrine therapy for the treatment of metastatic ER+ breast cancer. However, as for other cancer targeted therapies, all patients with metastatic disease on CDK4/6 inhibitors eventually progress, suggesting the development of mechanisms of acquired drug resistance that remain to be discovered. We propose a continuation project where we will investigate the effect of aberrant FGFR signaling on resistance to endocrine therapy in combination with CDK4/6 inhibitors in patients with ER+ breast cancer with the following aims: ? Aim 1: To elucidate the mechanisms by which FGFR1 amplification confers resistance to the combination of fulvestrant and CDK4/6 inhibitors in ER+/FGFR amplified breast cancers ? Aim 2: To conduct a phase Ib and a randomized phase II trial of the ER downregulator fulvestrant plus palbociclib the pan-FGFR inhibitor erdafitinib in patients with ER+/FGFR-amplified metastatic breast cancer ? Aim 3: To discover mechanisms of drug resistance in organoids derived from tumors progressing on CDK4/6 inhibitors. These will include: 1) tumors from patients progressing on treatment with fulvestrant/palbociclib erdafitinib in Aim 2, and 2) tumors from breast cancer patients on standard-of-care therapy with CDK4/6 inhibitors To our knowledge, this is the first time an FGFR inhibitor will be tested in combination with ER and CDK4/6 inhibitors in patients with breast cancer harboring FGFR amplification. A positive outcome of this clinical trial may provide women with FGFR-amplified/ ER+ breast cancer with a novel treatment option that does not include cytotoxic chemotherapy. Increased efficacy of the combination of fulvestrant, palbociclib and erdafitinib will also accelerate the development of FGFR inhibitors. We seek to identify biomarkers predictive of response to the combination that can be used in trials in appropriately selected patients with ER+ metastatic breast cancer. In addition, the comprehensive molecular analysis of organoids from cancers progressing on treatment provides an opportunity for the unbiased discovery of novel molecular mechanisms of drug resistance. These mechanisms, in turn, may represent actionable molecular targets that can be the focus of future drug discovery efforts and/or translational/clinical investigation in breast and other FGFR-dependent cancers. As such, the aims proposed herein may contribute to progress in the eradication of ER+ breast cancers.